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PDBsum entry 3c3c
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References listed in PDB file
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Key reference
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Title
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Molecular basis for the lack of enantioselectivity of human 3-Phosphoglycerate kinase.
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Authors
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C.Gondeau,
L.Chaloin,
P.Lallemand,
B.Roy,
C.Périgaud,
T.Barman,
A.Varga,
M.Vas,
C.Lionne,
S.T.Arold.
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Ref.
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Nucleic Acids Res, 2008,
36,
3620-3629.
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PubMed id
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Abstract
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Non-natural L-nucleoside analogues are increasingly used as therapeutic agents
to treat cancer and viral infections. To be active, L-nucleosides need to be
phosphorylated to their respective triphosphate metabolites. This stepwise
phosphorylation relies on human enzymes capable of processing L-nucleoside
enantiomers. We used crystallographic analysis to reveal the molecular basis for
the low enantioselectivity and the broad specificity of human 3-phosphoglycerate
kinase (hPGK), an enzyme responsible for the last step of phosphorylation of
many nucleotide derivatives. Based on structures of hPGK in the absence of
nucleotides, and bound to L and d forms of MgADP and MgCDP, we show that a
non-specific hydrophobic clamp to the nucleotide base, as well as a water-filled
cavity behind it, allows high flexibility in the interaction between PGK and the
bases. This, combined with the dispensability of hydrogen bonds to the sugar
moiety, and ionic interactions with the phosphate groups, results in the
positioning of different nucleotides so to expose their diphosphate group in a
position competent for catalysis. Since the third phosphorylation step is often
rate limiting, our results are expected to alleviate in silico tailoring of
L-type prodrugs to assure their efficient metabolic processing.
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